ACRIN PA 4005: Multicenter
Randomized Controlled Study of
a Rapid ‘Rule-out’ Strategy Using
CT Coronary Angiogram Versus
Traditional Care for Low-Risk ED
Patients with Potential ACS
Harold Litt MD-PhD
University of Pennsylvania
Philadelphia, PA
Disclosures and Funding
• Grant funding from Siemens Medical Solutions for
unrelated CT projects
• This project is funded, in part, under a grant with the
Pennsylvania Department of Health (SAP4100042725).
The Department specifically disclaims responsibility for
any analyses, interpretations or conclusions.
• Additional funding was obtained from the American
College of Radiology Imaging Network (ACRIN)
Foundation. The study was organized and coordinated
by ACRIN, which receives funding from the National
Cancer Institute (U01 CA079778 and U01 CA080098).
Introduction 1
• Patients presenting to EDs with symptoms
of potential ACS are a diagnostic dilemma
– Many admitted for “rule-out”, few will have a
cardiac diagnosis
– High cost to society, inefficient resource use
– Biomarkers and decision rules can not
exclude ACS with sufficient accuracy
• A negative cath means low event risk
Papanicolaou MN, et al. Am J Cardiol 1986;58:1181-1187.
Pitts WR, et al. Am J Cardiol. 1997;80:1086-1087.
Introduction 2
• Coronary CTA has high NPV for CAD
• Previous ED studies of CCTA have shown
– Low event rate for pts with no or min disease
– Efficiency compared to SPECT-MPI
– Potential cost savings vs. SPECT-MPI
• No previous study had sufficient power to
demonstrate acceptable safety endpoint
– <1% rate of 30-day MACE for neg “rule-out”
Introduction 3
• Observational trials and single center RCT
– ROMICAT 368 pts, 50% neg CT, no ACS
– Hollander et. al, 568 pts, no MACE w/neg CT
– Goldstein et. al, 197 pts, LOS & cost, no MACE
• Multicenter RCT - CT-STAT
–
–
–
–
699 pts at 16 sites – CT vs. SPECT-MPI
54% reduction in time to diagnosis
38% cost savings
MACE after negative test
• 2/268 CT (0.75%, 95% CI 0.09-2.7%)
• 1/266 SPECT-MPI (0.38%, 95% CI 0.01-2.1%)
Methods 1
• Multicenter RCT of CCTA based strategy
vs. traditional care (2:1) at 5 sites
• Primary hypothesis
– Patients without significant CAD by CCTA
have <1% rate of 30-day cardiac death or MI
• Secondary aims – CCTA vs. trad care
– ED discharge rate and length of stay
– 30-day MACE and revascularization
– 30-day resource utilization
Methods 2
• Eligibility criteria
– >30 yrs, signs/symptoms of potential ACS
– TIMI score 0-2, no acute ischemia on ECG
– Need for admission or testing to exclude ACS
• Exclusion criteria
– Clearly non-cardiac pain
– Comorbidity requiring hospital admission
– Normal cath or CCTA within previous year
– Contraindications to CCTA
– Post-randomization exclusions
• CrCl < 60 or subject received PE protocol CT
Methods 3 - Testing
• 64 slice or greater CT
– Noncontrast scan for calcium scoring
– Contrast enhanced CCTA
– Use of β-blockers and NTG per local protocol
– All readers ACC/AHA level 3
• Local interpretations for clinical decisions
• In analysis, stenosis quantified
– None, <50%, 50-69%, ≥70%
• Stress testing per local protocol
– Imaging or not, choice of modality
Methods 4 – Follow-up
• 30-day direct patient contact
– AMI, rehospitalization, revascularization
– Cardiac testing, cardiology visits, med use
• Record review
– All potential cardiac hospitalization
– All potential MACE
– If no direct patient contact
• Including neighboring hospitals
• SSDI if no other survival information
Methods 5 – Outcomes and Definitions
• All MACE reviewed by adjudication cmte
• Significant CAD
– ≥50% stenosis in LM, LAD, CX, RCA or
1st order branches
– Study indeterminate if non-diagnostic
segment and no significant CAD elsewhere
• ACS – AMI or confirmed unstable angina
– Reversible ischemia or ≥ 70% stenosis at cath
Results 1
• 1392 subjects July 2009 – Nov 2011
– 22 removed post-randomization (most CrCl)
– 908 randomized to CCTA, 462 traditional care
– Groups well matched, 60% black
Results 2 – Index visit testing
• 16% didn’t get CT
– 7-33% across sites
– Elevated HR (27%)
• Similar cath rate
– CT higher pos rate
• No testing
– 9% vs. 36%
Results 3 - Safety
• No 30-day MACE in 640 pts with neg CTA
– 0% event rate, 95% CI 0–0.57%
• Secondary aims - 30-day CCTA vs. trad
• One serious AE in each arm
– Bradycardia related to meds for HR control
Results 4 – Efficiency
• CCTA more often discharged from ED
– 50% vs. 23% (95% CI 21.4-33.2)
• LOS shorter
– Overall CCTA vs. trad care: 18 vs. 25 hrs*
– Negative testing: 12 vs. 25 hrs*
– Per protocol (had CCTA or stress testing)
• Overall 15 vs. 26 hrs*
• Negative CCTA or stress (trad care) 12 vs. 25 hrs*
*p<0.001
• More CCTA pts diagnosed with CAD
– 9.0 vs. 3.5% (95% CI 0-11.2)
Results 6 – Resource Utilization
• No significant differences in 30-day
resource utilization (CCTA vs. trad care)
Use of Resources
CCTA-based (%)
Traditional Care
(%)
95% CI for
Difference
Catheterization
5.1
4.2
-4.8 to 6.6
Revascularization
2.7
1.3
-4.3 to 7.0
Repeat ED visit
8.0
7.5
-5.2 to 6.2
Re-hospitalization
3.1
2.4
-4.9 to 6.4
Cardiologist visit
7.1
3.8
-2.4 to 9.0
• We are obtaining 1 year follow-up
Discussion 1
• CCTA-based strategy safe and efficient
– Upper limit of CI for 30-day MACE < 1%
– Increased rate of ED discharge, shorter LOS
– Fewer negative caths, more CAD diagnoses
• Previous trials results similar but
– Observational or no comparison arm
– RCTs not large enough to demonstrate
acceptable safety
– Wider range of trad care in our trial
– “Real world” management and disposition
Discussion 2 - Limitations
• Comparative RCT needs ~50,000 subjects
– Low event rate in population studies
– Study powered for conservative safety goal
• Need for any testing in these patients
– Enrolled only those needing admission/testing
– Still 9% vs. 36% didn’t get tested
• Low to intermediate risk only
– Can’t extrapolate to higher risk groups
Discussion 3 – CT Limitations
• Radiation exposure – tracked in study
– Very technology dependent
– Most CCTA now lower dose than SPECT-MPI
• 16% randomized to CCTA didn’t get it
– Elevated HR most common cause (27%)
– Very technology dependent,  over time
• More diagnosed with incidental CAD
– Better prevention or more testing?
Conclusions
• CCTA as first test for low-intermediate risk
pts presenting to EDs with potential ACS
• Safety
• Efficiency
– Increased ED discharge rates
– Reduced length of stay
• Long term follow-up needed
– Resource utilization
– Effects of CAD diagnosis on outcomes
Acknowledgements 1
• Hospital of the University of Pennsylvania
– Site Investigators: Judd E. Hollander, MD, Harold I. Litt, MD, PhD
– Research Coordinators: Emily Barrows, Jeffrey Le, Shannon
Marcoon, Julie Pitts, RN, Scott Steingall, RT
• Penn State University Medical Center at Hershey
– Site Investigators: James M. Leaming, MD, Harjit Singh, MD,
Michelle A. Fischer, MD, Steven Ettinger, MD, Carlos Jamis-Dow,
MD, Kevin Moser, PhD
– Research Coordinators: Swati Shah, Kevin Gardner, RN, Russell
Dicristina, Susan Oskorus
• Penn Presbyterian Medical Center
– Site Investigators: Laurence Gavin, MD, Anna Marie Chang, MD
– Research Coordinators: Christopher Decker, Michael Green,
Katie O’Conor, Angela Roach, Kristy Walsh, Max Wayne
Acknowledgements 2
• Wake Forest University
– Site Investigators: J. Jeffrey Carr, MD, MSc, Daniel W. Entrikin,
MD, Kim Askew, MD, James W. Hoekstra, MD, Simon Mahler,
MD, Chadwick D. Miller, MD, MS
– Research Coordinators: Denise Boyles, Stephanie Bradshaw,
Mark Collin, Erin Harper, Lisa Hinshaw, MS, Jane Kilkenny,
Megan Koonts, Lori Triplett, RN
• University of Pittsburgh Medical Center
– Site Investigators: Charissa B. Pacella, MD, Joan M. Lacomis,
MD and Christopher R. Deible, MD, PhD
– Research Coordinators: Sara Vandruff, Barbara Early, Tina Vita,
Dawn McBride
• Brown University: Biostatistical/research design
– Constantine Gatsonis, PhD, Brad Snyder, MS, Sanaa Boudhar,
MS, Patricia Fox, MS and Erin Greco, MS
Acknowledgements 3
• Data Safety Monitoring Board
– David Bluemke, MD, PhD (Chair), National Institute of Health;
Todd A. Alonzo, PhD, University of Southern California; Jon F.
Merz, MBA, JD, PhD, University of Pennsylvania; Herbert Y.
Kressel, MD, Beth Israel Deaconess Medical Center.
• Adjudication Committee
– W. Frank Peacock, MD, Cleveland Clinic; Robert Hendel, MD,
University of Miami
• Administration and Oversight – ACRIN Philadelphia
– Cynthia Olson, Anthony Levering, Cynthia Price, Maria Oh,
Patricia Blair, Martha Heckl, Charles Apgar, Mary Kelly, Mitchell
Schnall MD, PhD